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Am Large Hadron Collider und am ATLAS-Detektor werden umfangreiche Aufrüstungsarbeiten vorgenommen. Diese Arbeiten sind in mehrere Phasen gegliedert und umfassen unter Anderem Änderungen an der Ausleseelektronik der Flüssigargonkalorimeter; insbesondere ist es geplant, während der letzten Phase ihren Primärpfad vollständig auszutauschen. Die Elektronik besteht aus einem analogen und einem digitalen Teil: während ersterer die Signalpulse verstärkt und sie zur leichteren Abtastung verformt, führt letzterer einen Algorithmus zur Energierekonstruktion aus. Beide Teile müssen während der Aufrüstung verbessert werden, damit der Detektor interessante Kollisionsereignisse präzise rekonstruieren und uninteressante effizient verwerfen kann. In dieser Dissertation werden Simulationsstudien präsentiert, die sowohl die analoge als auch die digitale Auslese der Flüssigargonkalorimeter optimieren. Die Korrektheit der Simulation wird mithilfe von Kalibrationsdaten geprüft, die im sog. Run 2 des ATLAS-Detektors aufgenommen worden sind. Der Einfluss verschiedener Parameter der Signalverformung auf die Energieauflösung wird analysiert und die Nützlichkeit einer erhöhten Abtastrate von 80 MHz untersucht. Des Weiteren gibt diese Arbeit eine Übersicht über lineare und nichtlineare Energierekonstruktionsalgorithmen. Schließlich wird eine Auswahl von ihnen hinsichtlich ihrer Leistungsfähigkeit miteinander verglichen. Es wird gezeigt, dass ein Erhöhen der Ordnung des Optimalfilters, der gegenwärtig verwendete Algorithmus, die Energieauflösung um 2 bis 3 % verbessern kann, und zwar in allen Regionen des Detektors. Der Wiener Filter mit Vorwärtskorrektur, ein nichtlinearer Algorithmus, verbessert sie um bis zu 10 % in einigen Regionen, verschlechtert sie aber in anderen. Ein Zusammenhang dieses Verhaltens mit der Wahrscheinlichkeit fälschlich detektierter Kalorimetertreffer wird aufgezeigt und mögliche Lösungen werden diskutiert.:1 Introduction 2 An Overview of High-Energy Particle Physics 2.1 The Standard Model of Particle Physics 2.2 Verification of the Standard Model 2.3 Beyond the Standard Model 3 LHC, ATLAS, and the Liquid-Argon Calorimeters 3.1 The Large Hadron Collider 3.2 The ATLAS Detector 3.3 The ATLAS Liquid-Argon Calorimeters 4 Upgrades to the ATLAS Liquid-Argon Calorimeters 4.1 Physics Goals 4.2 Phase-I Upgrade 4.3 Phase-II Upgrade 5 Noise Suppression With Digital Filters 5.1 Terminology 5.2 Digital Filters 5.3 Wiener Filter 5.4 Matched Wiener Filter 5.5 Matched Wiener Filter Without Bias 5.6 Timing Reconstruction, Optimal Filtering, and Selection Criteria 5.7 Forward Correction 5.8 Sparse Signal Restoration 5.9 Artificial Neural Networks 6 Simulation of the ATLAS Liquid-Argon Calorimeter Readout Electronics 6.1 AREUS 6.2 Hit Generation and Sampling 6.3 Pulse Shapes 6.4 Thermal Noise 6.5 Quantization 6.6 Digital Filters 6.7 Statistical Analysis 7 Results of the Readout Electronics Simulation Studies 7.1 Statistical Treatment 7.2 Simulation Verification Using Run-2 Data 7.3 Dependence of the Noise on the Shaping Time 7.4 The Analog Readout Electronics and the ADC 7.5 The Optimal Filter (OF) 7.6 The Wiener Filter 7.7 The Wiener Filter with Forward Correction (WFFC) 7.8 Final Comparison and Conclusions 8 Conclusions and Outlook Appendices / The Large Hadron Collider and the ATLAS detector are undergoing a comprehensive upgrade split into multiple phases. This effort also affects the liquid-argon calorimeters, whose main readout electronics will be replaced completely during the final phase. The electronics consist of an analog and a digital portion: the former amplifies the signal and shapes it to facilitate sampling, the latter executes an energy reconstruction algorithm. Both must be improved during the upgrade so that the detector may accurately reconstruct interesting collision events and efficiently suppress uninteresting ones. In this thesis, simulation studies are presented that optimize both the analog and the digital readout of the liquid-argon calorimeters. The simulation is verified using calibration data that has been measured during Run 2 of the ATLAS detector. The influence of several parameters of the analog shaping stage on the energy resolution is analyzed and the utility of an increased signal sampling rate of 80 MHz is investigated. Furthermore, a number of linear and non-linear energy reconstruction algorithms is reviewed and the performance of a selection of them is compared. It is demonstrated that increasing the order of the Optimal Filter, the algorithm currently in use, improves energy resolution by 2 to 3 % in all detector regions. The Wiener filter with forward correction, a non-linear algorithm, gives an improvement of up to 10 % in some regions, but degrades the resolution in others. A link between this behavior and the probability of falsely detected calorimeter hits is shown and possible solutions are discussed.:1 Introduction 2 An Overview of High-Energy Particle Physics 2.1 The Standard Model of Particle Physics 2.2 Verification of the Standard Model 2.3 Beyond the Standard Model 3 LHC, ATLAS, and the Liquid-Argon Calorimeters 3.1 The Large Hadron Collider 3.2 The ATLAS Detector 3.3 The ATLAS Liquid-Argon Calorimeters 4 Upgrades to the ATLAS Liquid-Argon Calorimeters 4.1 Physics Goals 4.2 Phase-I Upgrade 4.3 Phase-II Upgrade 5 Noise Suppression With Digital Filters 5.1 Terminology 5.2 Digital Filters 5.3 Wiener Filter 5.4 Matched Wiener Filter 5.5 Matched Wiener Filter Without Bias 5.6 Timing Reconstruction, Optimal Filtering, and Selection Criteria 5.7 Forward Correction 5.8 Sparse Signal Restoration 5.9 Artificial Neural Networks 6 Simulation of the ATLAS Liquid-Argon Calorimeter Readout Electronics 6.1 AREUS 6.2 Hit Generation and Sampling 6.3 Pulse Shapes 6.4 Thermal Noise 6.5 Quantization 6.6 Digital Filters 6.7 Statistical Analysis 7 Results of the Readout Electronics Simulation Studies 7.1 Statistical Treatment 7.2 Simulation Verification Using Run-2 Data 7.3 Dependence of the Noise on the Shaping Time 7.4 The Analog Readout Electronics and the ADC 7.5 The Optimal Filter (OF) 7.6 The Wiener Filter 7.7 The Wiener Filter with Forward Correction (WFFC) 7.8 Final Comparison and Conclusions 8 Conclusions and Outlook Appendices

Cancer is the second leading cause of death after cardiovascular diseases in the world. Many of the chemical carcinogens need metabolic activation that catalyzed by cytochrome P450 and Phase II enzymes in order to exert their genotoxic and carcinogenic effects. Hence one possible mechanism is that phenolic compounds may alter anticarcinogenic effects is through an interaction with these enzymes either by the inhibition or activation of certain forms, leading to a reduced production of the ultimate carcinogen. Therefore anti-carcinogen activity of tannic acid, a hydrolyzable plant polyphenol, has a crucial importance to prevent conversion of pro-carcinogens to their carcinogenic form. Tannic acid is produced from secondary metabolism of plants and is found in edible vegetables, fruits and nuts, especially tea, cocoa, coffee and wine. In the present work, modulation of rabbit liver and kidney microsomal P450 dependent aniline 4-hydroxylase, N-nitrosodimethylamine N-demethylase and p-nitrophenol hydroxylase activities and cytosolic phase II enzymes / glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase:1 (NQO1) were studied in the presence of tannic acid at concentrations ranging from 0.5 &micro / M to 150 &micro / M in the reaction medium. The results obtained in this study were shown that tannic acid significantly inhibited the activities of p-nitrophenol hydroxylase, aniline 4-hydroxylase, NDMA N-demethylase, glutathione S-transferase, NAD(P)H:quinine oxidoreductase 1. Tannic acid was found to be the most potent inhibitor of cytosolic glutathione S-transferase with IC50 of 0.33 &micro / M and the least potent inhibitor of microsomal aniline 4-hydroxylase.with IC50 of 60.26 &micro / M. Effect of tannic acid on enzyme activities was further studied for both mode and type of inhibition. For this purpose various concentrations of the substrate were examined at various tannic acid concentrations. Lineweaver-Burk and Dixon plots were then generated from the resulting data sets. The Km value and inhibition constants (KI) were determined from double reciprocal and Dixon plot of the enzyme activity versus substrate and inhibitor concentration, respectively. Tannic acid was shown to be a noncompetitive inhibitor for liver cytosolic GST, NQO1 and microsomal aniline 4- hydroxylase enzymes with KI of 0.3 &micro / M, 41 &micro / M and 54.7 &micro / M, respectively. On the other hand, in kidney tissues, tannic acid was an uncompetitive inhibitor of cytosolic GST, while it was noncompetitive inhibitor for cytosolic NQO1 with a KI of 12.6 &micro / M. These results indicate that tannic acid may modulate cytochrome P450 dependent and Phase II enzymes and influence the metabolic activation of xenobiotics mediated by these enzymes.

Sulforaphane is an isothiocyanate found in high concentrations in cruciferous vegetables like broccoli. Sulforaphane has received much attention due to the evidence that it inhibits phase I carcinogen-bioactivating enzymes and/or induces phase II antioxidant enzymes as well as metallothioneins (MTs) (Perocco et al., 2006; Clarke et al., 2008; Yeh & Yen, 2009). Since MTs and antioxidant enzymes are involved in the scavenging of reactive oxygen species (ROS), the question was raised whether sulforaphane can provide protection against increased oxidative stress and if sulforaphane exposure of a human hepatocellular carcinoma cell line, like HepaRG cells, will have a negative impact on phase I and II biotransformation in these cells. Oxidative stress was exogenously induced in HepaRG cells with tert- Butyl hydroperoxide (t-BHP). Phase I and phase II biotransformation pathways were assessed with caffeine, paracetamol, aspirin, sodium benzoate, and paraaminobenzoic acid, respectively, as probe substances. Through the use of a liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) assay, the biotransformation of caffeine in phase I and the formation of paracetamol, aspirin, sodium benzoate and para-aminobenzoic acid conjugates in phase II were investigated. This involved elucidating the time it took for the whole probe to be completely biotransformed during phase I biotransformation and the unique conjugates formed during phase II biotransformation in HepaRG cells. The optimal t-BHP concentration and exposure time in HepaRG cells were standardized with a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. LC-ESI-MS/MS assays to monitor phase I and phase II biotransformation were optimized and validated. The optimal sulforaphane concentration and exposure time in HepaRG cells were standardized with a MTT assay. To evaluate the possible protective effect of sulforaphane against oxidative stress, HepaRG cells were pre-incubated with sulforaphane followed by the induction of oxidative stress with t-BHP and the quantification of the amount of viable cells with a MTT assay. To investigate the effect of sulforaphane on phase I and phase II biotransformation pathways, HepaRG cells were first pre-incubated with sulforaphane followed by the addition of a specific probe substance and the assessment of the biotransformation of the probe with a LC-ESI-MS/MS assay. The results partially supported the hypothesis of the study that sulforaphane will protect HepaRG cells against oxidative stress without negatively influencing phase I and phase II biotransformation. The results indicated that sulforaphane provided partial protection against t-BHP induced oxidative stress and had no effect on phase II paracetamol biotransformation in HepaRG cells. / Thesis, MSc (Biochemistry), North-West University, Potchefstroom Campus, 2013.

Sulforaphane is an isothiocyanate found in high concentrations in cruciferous vegetables like broccoli. Sulforaphane has received much attention due to the evidence that it inhibits phase I carcinogen-bioactivating enzymes and/or induces phase II antioxidant enzymes as well as metallothioneins (MTs) (Perocco et al., 2006; Clarke et al., 2008; Yeh & Yen, 2009). Since MTs and antioxidant enzymes are involved in the scavenging of reactive oxygen species (ROS), the question was raised whether sulforaphane can provide protection against increased oxidative stress and if sulforaphane exposure of a human hepatocellular carcinoma cell line, like HepaRG cells, will have a negative impact on phase I and II biotransformation in these cells. Oxidative stress was exogenously induced in HepaRG cells with tert- Butyl hydroperoxide (t-BHP). Phase I and phase II biotransformation pathways were assessed with caffeine, paracetamol, aspirin, sodium benzoate, and paraaminobenzoic acid, respectively, as probe substances. Through the use of a liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) assay, the biotransformation of caffeine in phase I and the formation of paracetamol, aspirin, sodium benzoate and para-aminobenzoic acid conjugates in phase II were investigated. This involved elucidating the time it took for the whole probe to be completely biotransformed during phase I biotransformation and the unique conjugates formed during phase II biotransformation in HepaRG cells. The optimal t-BHP concentration and exposure time in HepaRG cells were standardized with a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. LC-ESI-MS/MS assays to monitor phase I and phase II biotransformation were optimized and validated. The optimal sulforaphane concentration and exposure time in HepaRG cells were standardized with a MTT assay. To evaluate the possible protective effect of sulforaphane against oxidative stress, HepaRG cells were pre-incubated with sulforaphane followed by the induction of oxidative stress with t-BHP and the quantification of the amount of viable cells with a MTT assay. To investigate the effect of sulforaphane on phase I and phase II biotransformation pathways, HepaRG cells were first pre-incubated with sulforaphane followed by the addition of a specific probe substance and the assessment of the biotransformation of the probe with a LC-ESI-MS/MS assay. The results partially supported the hypothesis of the study that sulforaphane will protect HepaRG cells against oxidative stress without negatively influencing phase I and phase II biotransformation. The results indicated that sulforaphane provided partial protection against t-BHP induced oxidative stress and had no effect on phase II paracetamol biotransformation in HepaRG cells. / Thesis, MSc (Biochemistry), North-West University, Potchefstroom Campus, 2013.

Clinical drug trials are costly and time-consuming. Bayesian methods alleviate the inefficiencies in the testing process while providing user-friendly probabilistic inference and predictions from the sampled posterior distributions, saving resources, time, and money. We propose a dynamic linear model to estimate the mean response at each dose level, borrowing strength across dose levels. Our model permits nonmonotonicity of the dose-response relationship, facilitating precise modeling of a wider array of dose-response relationships (including the possibility of toxicity). In addition, we incorporate an adaptive approach to the design of the clinical trial, which allows for interim decisions and assignment to doses based on dose-response uncertainty and dose efficacy. The interim decisions we consider are stopping early for success and stopping early for futility, allowing for patient and time savings in the drug development process. These methods complement current clinical trial design research.

Le travail de cette thése a montré d'une part le rôle significatif du mécanisme de \underline{Fusion-Fission Asymétrique} dans les collisions entre ions lourds légers (A$_{\rm NC} \le$60) et, d'autre part, le \underline{Désalignement des Spins} dans un systéme {\it oblate-oblate} mettant en évidence pour \underline{la premiére fois le {\it mode papillon} lors de la réaction dans les résonances quasi-moléculaires}. Ces deux aspects, l'un macroscopique l'autre beaucoup plus lié á des effets microscopiques, sont certes différents d'un point de vue conceptuel, mais tout á fait complémentaires pour une compréhension globale des systémes di-nucléaires. \par \hspace*{0.5cm}Dans la premiére partie, les réactions $^{35}$Cl $+$ $^{12}$C et $^{35}$Cl $+$ $^{24}$Mg á 8 MeV/nucléon (expérience effectuée á Saclay) ont fait l'objet de mesures inclusives et de mesures exclusives. La nature des produits donnant naissance au mécanisme de fusion-fission asymétrique a été vérifiée. Il a été également démontré que dans ce domaine en énergie le processus \underline{ternaire} est trés faible. La deuxiéme partie est consacrée á l'étude de la réaction $^{28}$Si $+$ $^{28}$Si réalisée sur une énergie de résonance E$_{\rm lab.}$~=~111.6 MeV auprés de l'accélérateur VIVITRON de Strasbourg avec le multidétecteur EUROGAM Phase II. Le moment angulaire J$^{\pi}$ = 38$^{+}$ a été mesuré pour les voies inélastique et mutuelles de la voie de sortie $^{28}$Si $+$ $^{28}$Si. La mise en évidence du \underline{désalignement} \underline{des spins} a été interprété á l'aide du modéle moléculaire par le \underline{mouvement papillon}''mouvement Butterfly''. La spectroscopie $\gamma$ semble indiquer une nouvelle transition $\gamma$ dans la désexcitation du $^{32}$S qui est $0^{+} (8507.8\ keV) \to 2^{+}_{1} (2230.2\ keV) $.

The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.